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Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases

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Abstract

Efforts to develop neurotrophic factors to restore function and protect dying neurons in chronic neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s (PD) have been attempted for decades. Despite abundant data establishing nonclinical proof-of-concept, significant delivery issues have precluded the successful translation of this concept to the clinic. The development of AAV2 viral vectors to deliver therapeutic genes has emerged as a safe and effective means to achieve sustained, long-term, targeted, bioactive protein expression. Thus, it potentially offers a practical means to solve those long-standing delivery/translational issues associated with neurotrophic factors. Data are presented for two AAV2 viral vector constructs expressing one of two different neurotrophic factors: nerve growth factor (NGF) and neurturin (NRTN). One (AAV2-NGF; aka CERE-110) is being developed as a treatment to improve the function and delay further degeneration of cholinergic neurons in the nucleus basalis of Meynert, the degeneration of which has been linked to cognitive deficits in AD. The other (AAV2-NRTN; aka CERE-120) is similarly being developed to treat the degenerating nigrostriatal dopamine neurons and major motor deficits in PD. The data presented here demonstrate: (1) 2-year, targeted, bioactive-protein in monkeys, (2) persistent, bioactive-protein throughout the life-span of the rat, and (3) accurately targeted bioactive-protein in aged rats, with (4) no safety issues or antibodies to the protein detected. They also provide empirical guidance to establish parameters for human dosing and collectively support the idea that gene transfer may overcome key delivery obstacles that have precluded successful translation of neurotrophic factors to the clinic. More specifically, they also enabled the AAV-NGF and AAV-NRTN programs to advance into ongoing multi-center, double-blind clinical trials in AD and PD patients.

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Acknowledgments

We acknowledge the assistance of Jillyne R. Zeller, Robert B. Boyd, and the staff of Northern Biomedical Research, Inc. (Muskegon, Michigan) for conducting, under contract and our protocol, the dosing, in-life, and necropsy components of Experiment 1. We would also like to thank Eva K. Hofer, Marie Printz, Brian Kruegel, Katie Auble, Tiffany Baumann, Dawn Gammon, Richard Lin, and Christopher Wilson of Ceregene, Inc. for the expert technical assistance and Jeffrey Ostrove for the continuous support as well as comments on earlier drafts. We are grateful to Jim Conner (UCSD) for providing the NGF antibody for immunohistochemistry in Experiment 1. Finally, the assistance of Anna-Marie Baca in the preparation and submission of this paper is appreciated and acknowledged. Portions of Experiment 1 were supported by SBIR grants 1R43NS44652-1 and 1R43NS44652-2 to Ceregene.

Authors’ disclosure statement

All authors are current or past employees of Ceregene, Inc. except JHK, who is a member of the Ceregene, Inc. scientific advisory board and has a financial interest in the company.

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  1. Ceregene, Inc., 9381 Judicial Drive, Suite 130, San Diego, CA, 92121, USA

    Christopher D. Herzog, Kathie M. Bishop, Lamar Brown, Alistair Wilson & Raymond T. Bartus

  2. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA

    Jeffrey H. Kordower

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  1. Christopher D. Herzog
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Correspondence to Raymond T. Bartus.

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Herzog, C.D., Bishop, K.M., Brown, L. et al. Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. Drug Deliv. and Transl. Res. 1, 361–382 (2011). https://doi.org/10.1007/s13346-011-0037-z

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